White matter stroke is a common problem in the elderly population and makes up one third of all ischemic stroke cases. Infarcts that occur in the subcortical white matter tracts lead to demyelinating injury and progressive loss of axons. Stroke causes localized process of white matter cell death but also a subsequent regenerative response with the activation of white matter progenitors. This process of post-stroke progenitor response may contribute to post-stroke recovery and reduce the burden of stroke. As part of the preliminary studies for this grant, we have developed a white matter stroke model in mice to study the endogenous mechanisms of white matter repair after stroke. This model will allow identification of responsive white matter progenitor pools, their anatomical origin, the course of regeneration and their cellular fate. The proposed research in here will seek to delineate the aforementioned issues specific to white matter stroke. We will utilize a reporter mouse line, which will provide spatial and temporal restrictions needed for our studies. The overarching goal of this proposal is to identify molecular systems that modulate post-stroke white matter repair with the use novel gene expression studies. Although post-stroke oligodendrocyte regeneration may represent an attempt by the brain for endogenous white matter repair, the role of molecular systems involved in this process has been unclear. Our goal is to identify signaling systems pertinent to white matter regeneration that may serve as endogenous mediators of post-stroke remyelination, and through this role improve functional recovery after stroke. As there are currently no treatments to promote post-stroke white matter recovery, such signaling systems may be valuable targets not only for stroke but also in other demyelinating diseases. ! PUBLIC HEALTH RELEVANCE: Stroke causes damage to the brain by interrupting blood flow, and is the leading cause of adult disability in the United States. This proposal will investigate signals in the brain that may recruit new brain cells to regions known as white matter after stroke, and thereby improve the damaged white matter area. Since there are currently no effective treatments to improve functional recovery after human stroke, knowledge of the mechanisms that new white matter cells use to repopulate and repair damaged regions may help to design new treatments to reduce the devastating burden of this disease.